Over the last decade, small non-coding RNA molecules (~ 20 - 30 nucleotide nt]) have emerged as critical regulators in the expression and function of eukaryotic genomes. The regulation can occur at several important levels of genome function including chromatin structure, chromosome segregation, transcription, RNA processing, RNA stability, and translation. The central theme underlying regulation is that the small RNAs serve as specificity factors that direct effector proteins to target nucleic acid molecules via base-pairing interactions. The categories of small RNAs that have been investigated extensively are the smal interfering RNAs (siRNAs) and microRNAs (miRNAs). While miRNAs have been defined as regulators of endogenous genes, siRNAs are described as defenders of genome integrity in response to foreign or invasive nucleic acids such as viruses, transposons, and transgenes. Both categories of RNAs act in somatic lineages in a broad range of eukaryotic species. It has been suggested that virus infections and disease outcome may also be shaped by small RNAs. This has prompted us to hypothesize that HIV infection alters the endogenous miRNA expression patterns, thereby contributing to neuronal deregulation and AIDS dementia. In support of this hypothesis, we initiated studies to examine the impact of a viral protein (HIV-1 Tat) on miRNAs expression due to its characteristic features such as release from the infected cells and also uptake by diverse cell types. Hence, Tat has the potential to cause damage both in infected and uninfected cells. Interestingly, using primary human cultures of neurons, neuronal cell line, human brain tissues and brains of Tat-transgenic mice, our data show that Tat affected the expression of several miRNAs (e.g. miR-34a) as well as their target genes (e.g. CREB) that are involved in neuronal functions as shown in the model below. Based on that, we propose to investigate the involvement of these regulated miRNAs as well as the cellular factors in the context of HIV-1 associated neurological disease by using in vitro and in vivo animal models. Outcome from these studies will serve to prevent and/or delay neuronal deregulation and disorders observed in AIDS patients.